ISSN 1880-7151

熊本大学医学部保健学科

紀要第12号 （2016）

目

次

総説
子宮頚癌の分子生物学的発生機序 ------------------------- 吉本賢史

熊本大学医学部保健学科

他----- 1⇃ᮏ኱Ꮫ་Ꮫ㒊ಖ೺Ꮫ⛉⣖せ➨ 12 ྕ㸦2016㸧    ྜྷᮏ㈼ྐ ௚⥲ ㄝᏊᐑ㢁⒴ࡢศᏊ⏕≀ᏛⓗⓎ⏕ᶵᗎྜྷᮏ㈼ྐ  ᚨ⏣ⵇ  ᰡ἟⿱஧ 

Molecular carcinogenesis of cervical cancer
Masafumi Yoshimoto*, Aoi Tokuda**, Yuji Yaginuma***
Key words: cervical, cancer, HPV, carcinogenesis, geneticsཷ௜᪥ ᖺ ᭶ ᪥ ᥇ᢥ᪥ ᖺ ᭶ ᪥⇃ᮏ኱Ꮫ኱Ꮫ㝔ಖ೺Ꮫᩍ⫱㒊⇃ᮏ኱Ꮫ་Ꮫ㒊ಖ೺Ꮫ⛉᳨ᰝᢏ⾡⛉Ꮫᑓᨷ⇃ᮏ኱Ꮫ኱Ꮫ㝔⏕࿨⛉Ꮫ◊✲㒊ᵓ㐀ᶵ⬟ゎᯒᏛᢞ✏㈐௵⪅ᰡ἟⿱஧yaginuma@kumamoto-u.ac.jp

I. ࡣࡌࡵ࡟

✀ᨻ⟇᥎㐍◊✲஦ᴗ࡜ࡋ࡚◊✲⌜ࡀ⤌⧊ࡉࢀࠊᏊᐑ
㢁⒴࣡ࢡࢳࣥ᥋✀ᚋࡢ⚄⤒㞀ᐖ࡟㛵ࡍࡿ἞⒪ἲࡢ☜ Ꮚᐑ㢁⒴ࡣࠊHPV (Human Papilloma Virus)ឤᰁ࡟ࡼ

❧࡜᝟ሗᥦ౪࡟ࡘ࠸࡚ࡢ◊✲ࡀ⌧ᅾ࡞ࡉࢀ࡚࠸ࡿࡀࠊ

ࡾ⏕ࡌࡿ⑌ᝈ࡛ࠊ඲ୡ⏺࡛ẖᖺ⣙ 53 ୓ேࡀデ᩿ࡉᡃࡀᅜࡢ⌧≧࡛ࡣࠊཌ⏕ປാ┬ࡣᏊᐑ㢁⒴࣡ࢡࢳࣥ

ࢀࠊ⣙ 27 ୓ேࡀṚஸࡋ࡚࠸ࡿ (WHO; http://www.

᥋✀ࢆ✚ᴟⓗ࡟່ࡵࡿࡇ࡜ࢆ୰Ṇࡋ࡚࠸ࡿࡓࡵࠊ࣡

who.int/hpvcentre/en/)ࠋ㏆ᖺࠊඛ㐍ᅜ࡛ࡣࣃࣃࢽࢥࣟ

ࢡࢳࣥ᥋✀⪅ࡀ⃭ῶࡋ࡚࠸ࡿࠋ

࢘ࢫࢡ࣮ࣜࢽࣥࢢࡢ᪋⾜࡟ࡼࡾᏊᐑ㢁⒴ࡢẚ㍑ⓗ᪩ 2008 ᖺ࡟ࣀ࣮࣋ࣝ㈹ࢆཷ㈹ࡋࡓ Harald zur Hausenᮇࡢẁ㝵࡛デ᩿ࡀ࡛ࡁࠊࡑࢀ࡟ຍ࠼࡚ HPV ࡟ᑐࡍࡿ༤ኈࡣࠊ1983-1984 ᖺ࡟Ꮚᐑ㢁⒴࠿ࡽ HPV16, 18 DNA

࣡ࢡࢳࣥ᥋✀ࡢᬑཬ࡟ࡼࡾᏊᐑ㢁⒴ࡣᖺࠎῶᑡഴྥ

ࢆ᳨ฟࡋࠊHPV ឤᰁࡀᏊᐑ㢁⒴ࢆⓎ⑕ࡉࡏࡿࡇ࡜ࢆ

࡟࠶ࡿࡀࠊⓎᒎ㏵ୖᅜ࡛ࡣࢫࢡ࣮ࣜࢽࣥࢢࡸ࣡ࢡࢳ

᫂ࡽ࠿࡟ࡋࡓ 2,3,4)ࠋࡲࡓ 1985 ᖺ࡟ࡣࠊᏊᐑ㢁⒴⣽⬊ࣥ᥋✀ࡀ☜❧ࡉࢀ࡚࠾ࡽࡎṚஸ⪅ᩘࡀቑຍࡋ࡚࠸ࡿ

ᰴ࠾ࡼࡧᝈ⪅᳨యࡼࡾ HPV E6, E7 ࡢⓎ⌧ࡀ᳨ฟࡉࡢࡀ⌧≧࡛࠶ࡿࠋࡑࡢࡓࡵᏊᐑ㢁⒴ࡣዪᛶࡢ⒴࡟ࡼ

ࢀࡓ 5)ࠋࡉࡽ࡟Ꮚᐑ㢁⒴⑓ኚࡢ 99%௨ୖ࡟ HPV DNA

ࡿṚஸཎᅉࡢ➨஧఩࡜࡞ࡗ࡚࠸ࡿ 1)ࠋ᪥ᮏ࡛ࡣࠊึ

ࡀ᳨ฟࡉࢀࡿ࡜࠸࠺ሗ࿌࠿ࡽࡶ HPV ࡜Ꮚᐑ㢁⒴ࡢ

஺ࡢపᖺ㱋໬࡟ࡼࡿ HPV ឤᰁࡢቑຍ࡟ࡼࡾ 20-30 ṓᐦ᥋࡞㛵ಀࡣ᫂ⓑ࡛࠶ࡿࡀࠊᐟ୺⣽⬊ࡢⓎ⒴࡟ࡣ

௦ࡢⱝ࠸ዪᛶ࡟Ꮚᐑ㢁⒴ࡀቑຍࡋ࡚࠸ࡿࡓࡵࠊ20 ṓ

HPV ឤᰁࡔࡅ࡛ࡣ୙༑ศ࡛ࠊᵝࠎ࡞㑇ఏᏊኚ␗ࡸ㑇௨ୖࡢዪᛶࡀᑐ㇟࡜࡞ࡾࠊࡲࡎ⣽⬊デ᳨ᰝࡀ⾜ࢃࢀࠊఏᏊ㓄ิࡢኚ໬ࢆకࢃ࡞࠸ DNA ኚ໬࡛࠶ࡿ࢚ࣆࢪ

␗ᖖࡀ࠶ࡿሙྜ࡟ࢥ࣏ࣝデཬࡧ⤌⧊デ (⭼ᣑ኱㙾ࢆ࢙ࢿࢸ࢕ࢵࢡ࡞␗ᖖࡶሗ࿌ࡉࢀ࡚࠸ࡿ 6,7)ࠋ౛࠼ࡤࠊ

⏝࠸࡚⒴ࡀ࡛ࡁࡸࡍ࠸Ꮚᐑཱྀ௜㏆ࢆほᐹࡋࠊ␗ᖖࡀ⒴ 㑇 ఏ Ꮚ ࡛ ࡣ PIK3CA (Phosphatidylinositol- 4,5-

␲ࢃࢀࡿሙྜࡣࡑࡢ㒊ศࢆ⏕᳨ࡍࡿ)ࡀ⾜ࢃࢀࡿࠋࡉ

Bisphosphateࡽ࡟ HPV ࣡ࢡࢳࣥ᥋✀ࡣࠊ2013 ᖺᗘ࠿ࡽᐃᮇண㜵(3q26.3;᥋✀ࡢᑐ㇟࡜࡞ࡗࡓࡀࠊ⛥࡟」ྜᛶᒁᡤ⑊③⑕ೃ⩌Transcriptase) (5p15.33; 33%)ࠊ c-myc (8q24; 25%)ࠊ

ࡸᛴᛶᩓᅾᛶ⬻⬨㧊⅖➼ࡢ๪స⏝ࡀሗ࿌ࡉࢀ࡚࠸ࡿࠋ

HER2 (Human Epidermal Growth Factor Receptor 2)ࡇࡢ๪཯ᛂ࡜࣡ࢡࢳࣥ᥋✀ࡢᅉᯝ㛵ಀࢆ᫂ࡽ࠿࡟ࡍ

(17q21.2; 29%) ࠊ Cyclin D1 (11q13.3; 12%) ࠊ cIAP1ࡿࡓࡵࠊཌ⏕ປാ┬ࡢ᪂⯆࣭෌⯆ឤᰁ⑕ཬࡧண㜵᥋(11q22; 18.5%)ࡢ㑇ఏᏊቑᖜࡸ Ras (Rat Sarcoma Viral-1-

3-Kinase,

Catalytic

43%) ࠊ hTERT

SubunitAlpha)(Telomerase

Reverse)F<#!#BE,#"&H= 12 02016    'F-1 ;R

LC(Transforming Growth Factor, Alpha), Cadherin13,

E6

KRT16 (Keratin 16, Type I)ǹ0ÆɦƕǴļ0șćE7

 > <

<

L1

E2

>

Ǩ,'$ 500 ź0ǴļșćǒƕČſǌ,E2

.'*B,EȺĢ*B 12) 0?/ļÖ

E1

HPV16

E6
6

E6

E7
7

E7

E4

L2

÷Æ1 HPV ɜȂBşŔĮȾ0ñōǲ¾>UivȪǪƖ/*ÆǴļ0¶Ɩȷ>ÆɦƕǴļ0ŽǟƠ

B,+ƜB,ū/ɏ@/.A((B

E2

ƼïĔ/B,@ @/ŶĮ. HPV >#E
E5

4   /:  

ļÖ÷Æ0ĿȿƓ

0ǆ0ȴļƜȳµǯŽ/È)$đ

A.>

ǯ.ZR{

7: HPV 1¿ſȈɃĨ DNA Ěƽ+ 6 (0ŧËǴļ (E1,gSȼȽ>ƅ$.ŇɯȦǯ0ȀǪȥɥȪù

E2, E4, E5, E6, E7), 2 (0ċËǴļ (L1, L2) ?3K

+B

J|Z DNA 0ȲƝ ǲŏEǣƦ Ƀě+1 HPV ½ƬļÖ÷ÆEÎ

B LCR @.B HPV½ƬŧË0Mm]t|.ſǌ+1
șćEɦƕ

B

ȼ

0ƴĤ:1

0 E2 ɲƤǚE2  E5, E6, E7 0ƜȳµǯÌŪ/(*¬Ƨȴļ

B

HPV Uiv0şŔĮȾUiv5
B,+ÎB$<ƴĤ:ċ1 E6, E7 șćĖŽǯ/ʀƋ

II. HPV / (*B

Oncogene Homolog)0¶Ɩȷ ÆɦƕǴļ+1

 HPV 1ɕ 8,000 ÈǊ0ȈɃĨ DNA KJ|Z+¢Żw`|/?BșćĆŰ PTEN (PhosphataseƚȈŝɒǉ0OoXeE=&And

TensinHomolog;58%) >

TSLC1

Ɇǹ/½Ƭ

(Tumor

Suppressor In Lung Cancer 1; 58%)ǹ/:@CBƖÇȏB ćİ9+/ɕ 120 Ŗ0 HPV șāC*B

8,9,10,11)

ȟȭ>ēĝ

6*0 HPV Ýǧ$¿ſ0Ui

4,5-Bisphosphate 3-Kinase, Catalytic Subunit Alpha)vĚƽE*B #C1 6 (0ŧËǴļ (E1, E2,(3q26.3;

E4, E5, E6, E7), 2 (0ċËǴļ (L1, L2) #*

43%)

hTERT

(Telomerase

Transcriptase) (5p15.33; 33%)

ReverseȢɄɖɲ/

c-myc (8q24; 25%)

HER2 (Human Epidermal Growth Factor Receptor 2)

ǣƦ(17q21.2; 29%)

B (Ǝ 1)13)

Cyclin D1 (11q13.3; 12%)cIAP1

ǝKJ|Z DNA 0ȲƝ>ǲŏE

B LCR (long control region)@ĚƗC*

(11q22; 18.5%)0ǴļƼȱ> Ras (Rat Sarcoma Viral
Oncogene Homolog)0¶Ɩȷ ÆɦƕǴļ+1

1. HPV 0ȴɶ¢Żw`|/?BșćĆŰ PTEN (Phosphatase HPV 1OoXeǘȘōEVeAnd

TensinHomolog;58%) >TSLC1

* Alessandro @1ȕɹ0ƺȀƖ/È)*òǺµǯ/ȴɶC*B

(Tumor

Suppressor In Lung Cancer 1; 58%)ǹ/:@CB@/

8,9,10,11)ƬļÖ÷ÆȨȷ,ƚŽļÖ÷

v-Myb,

CyclinB1,

B α-HPV ǂ1 ɰƖ0ƖÇʂʇEÎ
BĠ{ZRð HPV /ȴɶCB 14)ñōǲ¾Ɯ$ HPV ½ƬĮȾ+1

CDKN2A/p16,

ɕ 30 Ŗ0 HPV ǂēĝ>ƖÇȏɆ/½Ǩ{ZRð HPV , ļÖ÷Æǹ0ƖŗʄñƗȐEɚȮ0³ĮȾ0Ǵļșć}q|EtJR~H}J+Ȟ´B L1 0Ǵļ

HPV /1 HPV6, 11 ǹǂ

TOP2A

Ǩ{ZRð

Ŕ/ʂʇ0ǆ/ƫñ

(Topoisomerase (DNA) II Alpha 170kDa), E2F1 (E2F

VY~tǹ0ɰƖŗʄEÎ

Transcription Factor 1), FOXM1 (Forkhead Box M1),

C*B īë/.'* Ǩ{ZRð HPV 

MCM2/4/5 (Minichromosome Maintenance Complex

ůń/Î$ĪșƖĊÕÇȊǽŗŴȨȷ@Component2/4/5), PTGES (Prostaglandin E Synthase)ǹ

ȔÆșŴ0ĮȾřËÄɻǴļ0șćʀƋ,

TGFβ1

DNA þŢC$ 15) 0ȺĢ1ȏɆ/½Ƭ

(Transforming

TGFα{ZRð HPV =șÆȐE=(,EňĦGrowthFactor,

Beta

1),

-2-

,ǜ@

#0ÆƴƁ@ HPV11 0 L1, E6, E7
BǨ

B k

⇃ᮏ኱Ꮫ་Ꮫ㒊ಖ೺Ꮫ⛉⣖せ➨ 12 ྕ㸦2016㸧    ྜྷᮏ㈼ྐ ௚ࣄࢺࡢᵝࠎ࡞⭘⒆࡬ࡢ㛵୚࡟ࡘ࠸࡚ࡢヲ⣽ࡣ୙࡛᫂ࡋࡓ HPV ࡣࠊ࢘࢖ࣝࢫ⺮ⓑ㉁ࡢ E2 ࡀึᮇ㑇ఏᏊ࡛࠶ࡿࠋ୍᪉ࠊ㧗ࣜࢫࢡᆺ HPV ࡟ࡘ࠸࡚ࡣࠊIARC

࠶ࡿ E5, E6, E7 ࡢⓎ⌧ࢆ┤᥋ᢚไࡋࠊHPV DNA ࢆ(International Agency for Research on Cancer)࡟ࡼࡾ 15࢚ࣆࢯ࣮࣐ࣝ (ᐟ୺⣽⬊ࡢᰁⰍయ࡟⤌㎸ࡲࢀࡎࠊ⎔✀ࡢ HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,≧࡞≧ែࡢࡇ࡜)࡞≧ែ࡛ẚ㍑ⓗపࢥࣆ࣮ᩘ (50-100

68, 73, 82)ࡀᐃ⩏ࡉࢀ࡚࠸ࡿࠋࡇࡢ࠺ࡕᏊᐑ㢁⒴ࡢཎ

ࢤࣀ࣒/⣽⬊)࡟⥔ᣢࡍࡿ 26)ࠋణࡋࠊഹ࠿࡟Ⓨ⌧ࡋ࡚ᅉࡣࠊHPV16 ࡀ༙ᩘࢆࠊHPV18 ᆺࡀ 10-20%ࢆ༨ࡵ

࠸ࡿ E5, E6, E7 ࡣឤᰁ⣽⬊ࡢቑṪ࡜㞄᥋ࡍࡿᇶᗏ⣽⬊࡬ࡢឤᰁࡢᣑ኱ࢆಁ㐍ࡍࡿࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿ

ࡿࡀࠊᏊᐑ㢁㒊⭢⒴࡛ࡣ HPV18 ࡀ⣙ 40%ࢆ༨ࡵࡿ
ࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿ

16,17)

ࠋࡲࡓ㧗ࣜࢫࢡᆺ HPV ࡣࠊ

27)ࠋᇶᗏ⣽⬊࠿ࡽศ໬ࡢ㐍ࢇࡔ⣽⬊ᒙ࡛ࡣ࢘࢖ࣝࢫ

Ꮚᐑ㢁⒴࡟ຍ࠼࡚⫠㛛⒴ࡸእ㝜⒴ࠊ㝜ⱼ⒴ࠊࡉࡽ࡟

ࢤࣀ࣒ࡢ」〇ࡀάⓎ࡟࡞ࡿࠋࡇࢀࡣ࢘࢖ࣝࢫ DNA ࡢཱྀ⭍⒴ࢆྵࡴ㢌㢁㒊⒴࡟ࡶ㛵୚ࡍࡿࡇ࡜ࡀሗ࿌ࡉࢀࠊ

」〇ࢆ⾜࠺ E1 (࣮࣊ࣜ࢝ࢮ), E2 (㌿෗ᅉᏊ)ࡢⓎ⌧ࡀ

ᵝࠎ࡞⒴ࡢ୰࡛᭱ࡶ㔜せ࡞ࣜࢫࢡᅉᏊࡢ㸯ࡘ࡜࡞ࡗᐟ୺⣽⬊ࡢศ໬౫Ꮡᛶ࡟ஹ㐍ࡋࠊᐟ୺⣽⬊ࡢ」〇⺮ࠋ43 ✀ࡢ HPV ࡀᒓࡍࡿ ȕ-HPV ᒓࡣࠊ㑇ⓑ㉁ࢆ฼⏝ࡍࡿࡇ࡜࡛࢘࢖ࣝࢫ DNA ࡢ」〇ࡀ⾜ࢃఏᛶ⑌ᝈࡢ␼㉕≧⾲⓶Ⓨ⫱␗ᖖ⑕ᝈ⪅ࡢ 30-60%࡟

ࢀࡿࡓࡵ࡛࠶ࡿࠋࡲࡓᚋᮇ㑇ఏᏊ L1, L2 ࡢⓎ⌧ࡶጞ⏕ࡌࡿ⓶⭵⒴࠿ࡽ㧗㢖ᗘ࡟ྠᐃࡉࢀࠊ㠀࣓ࣛࣀ࣮࣐

ࡲࡾࠊ࢝ࣉࢩࢻࡀᙧᡂࡉࢀࡿ 27)ࠋ୰ᒙ⣽⬊࡛ࡣ E6,ᛶ⓶⭵⒴࡟㛵୚ࡍࡿࡇ࡜ࡀ᫂ࡽ࠿࡟࡞ࡗ࡚࠸ࡿ 20)ࠋE7 ࡢⓎ⌧࡟ࡼࡾࠊᮏ᮶ࡣ⣽⬊࿘ᮇ࠿ࡽ⬺ࡋ࡚࠸ࡿࡣ

ࡉࡽ࡟೺ᖖ⪅ࡢ⓶⭵࡟ࡶ ȕ-HPV ᒓࡀከ㔞࡟Ꮡᅾࡋࠊ

ࡎࡢᐟ୺⣽⬊ࡢศ⿣ࡀಁ㐍ࡉࢀࡿࠋࡲࡓࡇࡢẁ㝵ࡢᢠ HPV ᢠయ࡜࢘࢖ࣝࢫ DNA ࣐࣮࣮࢝ࢆ⏝࠸ࡓ␿Ꮫᐟ୺⣽⬊࡛ࡣ E4 Ⓨ⌧ࡀࡳࡽࢀࠊ⣽⬊࿘ᮇࡢ S ᮇࡲㄪᰝ࡛ࡣࠊ㠀㑇ఏᛶ⓶⭵⒴ࡢ᪤ ⪅ࡣ ȕ-HPV ᒓࡢឤࡓࡣ G2 ᮇ࡟࠶ࡿࡇ࡜ࡀ≉ᚩ࡛࠶ࡿ 28)ࠋࡉࡽ࡟ศ໬

ᰁ⋡ࡀ㧗࠸ࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿ 21,22)ࠋȕ-HPV ᒓࡣࡢ㐍ࢇࡔୖᒙࡢ⣽⬊࡛ࡣࠊ᭱ୖᒙ࡟఩⨨ࡍࡿୖ⓶⣽⓶⭵⒴ࡢ๓⒴⑓ኚ࡛࠶ࡿ᪥ගゅ໬⑕ࡢẁ㝵࡛ DNA⬊ࡀ⣽⬊Ṛࡍࡿࡇ࡜࡛ᡂ⇍ࡋࡓ࢘࢖ࣝࢫ⢏Ꮚࡀᨺฟಟ᚟⺮ⓑ㉁ࢆ㜼ᐖࡋࠊUV ࡟ࡼࡿ DNA ᦆയࡢ⵳✚ࢆࡉࢀࡿࠋࡑࡋ࡚࢘࢖ࣝࢫ⢏Ꮚࡢ L1 ࡀ᪂ࡓ࡞ᐟ୺⣽࡚࠸ࡿ

18,19)

ᣍࡁࠊⓎ⒴࡟㛵୚ࡍࡿࡇ࡜ࡀ♧၀ࡉࢀ࡚࠸ࡿ

ࠋ⬊ࡢ⣽⬊⭷ୖࡢ࣊ࣃࣛࣥ◲㓟ࣉࣟࢸ࢜ࢢࣜ࢝ࣥࡸ࢖

23)ࣥࢸࢢࣜࣥ Į6 ࡟⤖ྜࡍࡿࡇ࡜࡛ࡑࡢ⣽⬊࡟ឤᰁࡋࠊ
2. HPV ࡜Ꮚᐑ㢁㒊⭘⒆ࡢᙧᡂ

L2 ࡸឤᰁ⣽⬊࢚ࣥࢻࢧ࢖ࢺ࣮ࢩࢫࡢാࡁ࡟ࡼࡾ⣽ ዪᛶࡢ୍⏕ᾭࡢ HPV ឤᰁࣜࢫࢡࡣ⣙ 80%࡛ࠊឤ⬊ෆ࡟࢘࢖ࣝࢫ⢏Ꮚࡀྲྀࡾ㎸ࡲࢀࡿ 29)ࠋᰁࡢࣆ࣮ࢡࡣ 25 ṓ࡛࠶ࡿࠋHPV ឤᰁ࡛ࡣ࢘࢖ࣝࢫ
⾑⑕ࡀ㉳ࡇࡽࡎࠊᐟ୺ࡢ⣽⬊Ṛࢆㄏᑟࡋ࡞࠸ࡓࡵ⅖

3. ᣢ⥆ឤᰁ࡜ච␿ᅇ㑊⑕཯ᛂࡀ㉳ࡁ࡞࠸ࠋࡑࡢࡓࡵᐟ୺ࡢච␿ᶵᵓࡀാࡁ

 HPV ឤᰁࡣච␿ᶵᵓ࡟ࡼࡾไᚚࡉࢀࠊࣄࢺࡣ୺࡟

࡟ࡃࡃࠊឤᰁࡀᣢ⥆ࡋࡸࡍ࠸࡜࠸࠺≉ᚩࡀ࠶ࡿࡀࠊ

࣊ࣝࣃ࣮T ⣽⬊ࢆ௓ࡋ࡚ HPV ឤᰁ⣽⬊ࡸ⑓ኚࢆ㝖

HPV ឤᰁࡢ኱㒊ศࡣ 1 ᖺ௨ෆ࡟᤼㝖ࡉࢀࠊHPV ឤཤࡍࡿ 30)ࠋࡑࡢࡓࡵ㛗ᮇⓗ࡞ HPV ࡢᣢ⥆ឤᰁࡢࡓᰁ࡛⏕ࡌࡓ๓⒴⑓ኚࡶ⣙ 3 ᖺ௨ෆ࡟⮬↛἞⒵ࡍࡿࠋ

ࡵ࡟ࡣࠊHPV ࡀᵝࠎ࡞ᶵᗎ࡛ᐟ୺⣽⬊ࡢච␿ᶵᵓࢆ

ࡋ࠿ࡋ HPV ឤᰁ⪅ࡢ⣙ 10%࡛ 3 ᖺ௨ୖࡢᣢ⥆ឤᰁᅇ㑊ࡍࡿࡇ࡜ࡀᚲせ࡜࡞ࡿࠋ౛࠼ࡤࠊ㧗␗ᆺࡢᏊᐑ

ࡀᡂ❧ࡋࠊࡉࡽ࡟ࡑࡢ୍㒊࠿ࡽᩘ༑ᖺᚋ࡟Ꮚᐑ㢁⒴㢁㒊⑓ኚࡸᏊᐑ㢁㒊ୖ⓶ෆ⭘⒆࡛ࡣࠊHLA ཷᐜయ࡬

ࡀⓎ⑕ࡍࡿ

1,24)

ࠋ

ࡢᢠཎᥦ♧ࢆ㜼ᐖࡍࡿࡇ࡜࡛ࠊච␿┘ど࠿ࡽ㏨ࢀࡿ

 HPV ࡢ⏕άྐࡣ௚ࡢ࢘࢖ࣝࢫ࡜ࡣ␗࡞ࡾ⊂≉࡛ࠊࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿ 27)ࠋHPV ࡀឤᰁࡋࡓᐟ୺⣽⬊ឤᰁࡋࡓᐟ୺⣽⬊ࡢศ໬㐣⛬࡜ᐦ᥋࡟㛵㐃ࡍࡿ 25)ࠋ࡛ࡣࠊE6 ࡢᙧ㉁㌿᥮ᶵ⬟ࢆ p16 ࡀ㜼ᐖࡋ࡚࠸ࡿࡇ࡜

㏻ᖖࠊᡥᖹୖ⓶⣽⬊ࡣᇶᗏᒙ࡟࠶ࡿᇶᗏ⣽⬊ࠊഐᇶࡀ▱ࡽࢀ࡚࠸ࡿࠋࡋ࠿ࡋ HPV ࡣ E7 ࢆ⏘⏕ࡍࡿࡇ࡜ᗏ⣽⬊ࡀቑṪࡋࠊࡑࡢᚋࡣ୰ᒙ⣽⬊ࠊ⾲ᒙ⣽⬊࡬࡜࡛ Rb ࡢ୙ά໬࡜ࢧ࢖ࢡࣜࣥ A/E ࡢάᛶ໬ࢆᘬࡁ㉳ศ໬ࡋࠊ⣽⬊ࡣ᭱⤊ⓗ࡟Ṛ⁛ࡍࡿࠋࡑࡢࡓࡵ HPV ࡣࠊࡇࡋࠊࡑࡢ⤖ᯝ p16 ࡣ୙ά໬ࡉࢀࠊE6 ࡣ p16 ࡢ㜼ᐖ⮬㌟ࢆ⥔ᣢࡍࡿࡓࡵࠊᚤᑠ࡞യ࡟ࡼࡗ࡚㟢ฟࡋࡓᇶస⏝࠿ࡽ㏨ࢀࡿࡇ࡜ࡀ࡛ࡁࡿ 30)ࠋࡲࡓ HPV E6 ࡣࠊᗏᒙࡢ⣽⬊࡟ឤᰁࡍࡿᚲせࡀ࠶ࡿࠋᇶᗏ⣽⬊࡟ឤᰁp16 㜼ᐖ⺮ⓑ㉁ࡢ SERTAD1 ࡜⤖ྜࡋࠊSERTAD1 ࢆ-3-)F<#!#BE,#"&H= 12 02016    'F-1 ;* $

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31,32)¾EƾƋ

BȐƖ=Ĝ@C*B/*p16 0Ƶ«ıɣ@ǼC$Ġ{ZRðə0?

 ½ƬŧË0şŔĮȾ+1 E2 ŧËǴļ0o~x^+B p97 Eɦƕ

HPV E6 1 Tyk2 (Tyrosine Kinase 2) > IRF-3(Interferon Regulatory Factor-3)EB,+ E6, E7 0șćEɦƕ @/ E6, E7 ǘȘō5ǥƥúġ

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III. HPV ࡢⓎ⒴ᶵᗎ

5. Ꮚᐑ㢁㒊⭘⒆ࡢᙧᡂ
 Ꮚᐑ㢁⒴ࡣ๓⒴≧ែ࡛࠶ࡿ␗ᙧᡂ࠿ࡽୖ⓶ෆ⒴ࠊ
ᾐ₶⒴࡬࡜㐍⾜ࡍࡿࡇ࡜ࡀ▱ࡽࢀ࡚࠸ࡿ (ᅗ 2)ࠋ␗

 HPV ࡢឤᰁࡋࡓᇶᗏ⣽⬊ෆ࡛ E2 Ḟኻࢆక࠺ HPV

ᙧᡂࡣࠊCIN (cervical intraepithelial neoplasia; Ꮚᐑ㢁DNA ࡢࣄࢺࢤࣀ࣒࡬ࡢ⤌㎸ࡳࡀ㉳ࡇࡿ࡜ࠊE2 ࡟ࡼ㒊ୖ⓶ෆ⭘⒆)ศ㢮࡟ࡼࡾࠊୖ⓶ᒙࡢୗ 1/3 ࡟࠾࠸࡚ࡾⓎ⌧ࡀᢚไࡉࢀ࡚࠸ࡓ E6, E7 ࡀ㧗Ⓨ⌧ࡋࠊ⣽⬊࿘⣽⬊࡟␗ᆺࡀࡳࡽࢀࡿ㍍ᗘ␗ᙧᡂ (CIN1)ࠊୖ⓶ᒙࡢᮇไᚚࠊ࢔࣏ࢺ࣮ࢩࢫࠊDNA ಟ᚟ࠊ⣽⬊⪁໬ࠊ⣽⬊

ୗ 2/3 ࡢ⣽⬊࡟␗ᆺࡀࡳࡽࢀࡿ୰ᗘ␗ᙧᡂ (CIN2)ࠊ

ศ໬➼ࡢ⣽⬊ෆࡢᵝࠎ࡞⒴ᢚไᶵᵓࡢ◚⥢ࡸᐟ୺⣽␗ᆺ⣽⬊ࡀୖ⓶඲ᒙ࡟࠾ࡼࡪ㧗ᗘ␗ᙧᡂ࡜ୖ⓶ෆ⒴⬊ࡢࢤࣀ࣒୙Ᏻᐃᛶࡢㄏᑟ࡟ࡼࡾᐟ୺⣽⬊ࡢᝏᛶ໬

ࠋCIN ࡣ㐃⥆ⓗ࡞ኚ໬࡛࠶ࡾࠊ

ࡀಁ㐍ࡍࡿࠋࡇࡢࡼ࠺࡟ E6, E7 ࡜࠸࠺ 2 ࡘࡢ࢘࢖ࣝ

ࡑࡢ㐍⾜࡟ࡣ HPV ࡀⓎ⌧ࡍࡿ E6, E7 ࢆ୰ᚰ࡜ࡋࡓ

ࢫ DNA ࡣ⒴ಁ㐍ⓗ࡟ᶵ⬟ࡍࡿࡇ࡜ࡀ▱ࡽࢀ࡚࠸ࡿࠋ

(CIN3)࡟ศ㢮ࡉࢀࡿ39)࢘࢖ࣝࢫ⺮ⓑ㉁ࡀ㔜せ࡛࠶ࡿࠋHPV ࡣࠊᇶᗏ⣽⬊࡬ࡢឤᰁึᮇ࡛ࡣ⮬㌟ࡢ࢘࢖ࣝࢫ DNA ࡢⓎ⌧ࢆᢚไ

1. E6 ࡢⓎ⒴⬟ࡋ࡚࠸ࡿࡀࠊCIN2/3 ࡢẁ㝵࡛࡯࡜ࢇ࡝ࡢ㧗ࣜࢫࢡᆺ E6 ࡣ⣙ 150 ಶࡢ࢔࣑ࣀ㓟࠿ࡽ࡞ࡿࢩࢫࢸ࢖ࣥࣜ

HPV ࡀᐟ୺⣽⬊࡬⤌㎸ࡲࢀ (HPV 18 DNA ࡣࠊ࡯ࡰࢵࢳ࡞⺮ⓑ㉁࡛ࠊ᰾࠾ࡼࡧ⣽⬊㉁࡟ᒁᅾࡍࡿࠋ㧗ࣜ

඲࡚ࡢ CIN2/3 ࡛ᐟ୺⣽⬊࡬ࡢ⤌㎸ࡳࡀࡳࡽࢀࡿࡀࠊ

ࢫࢡᆺ࡜పࣜࢫࢡᆺࡢ㐪࠸ࡢ୍ࡘ࡟ E6 ࡢᒁᅾࡢ㐪

HPV16 DNA ࡢሙྜࠊ୍㒊ࡢᾐ₶⒴࡛ࡣ࢚ࣆࢯ࣮࣐

࠸ࡀᣲࡆࡽࢀࠊ౛࠼ࡤࠊపࣜࢫࢡᆺ HPV E6 ࡣ⣽⬊ࣝ࡞≧ែ᳨࡛ฟࡉࢀࡿࡇ࡜ࡀ࠶ࡿ)ࠊᏳᐃⓗ࡟㧗Ⓨ⌧㉁࡟ᒁᅾࡋ p53 ࡢ᰾࡬ࡢ⛣⾜ࢆ㜼ᐖࡍࡿࡀࠊ㧗ࣜࢫ

ࡋࡓ E6, E7 ࡀ p53 ࡸ Rb ➼ࡢ⒴ᢚไᶵᵓࢆ◚⥢ࡉࡏࠊࢡᆺ HPV E6 ࡣ p53 ࡢศゎࢆಁ㐍ࡍࡿࠋE6 ࡣ zinc ⤖ຍ࠼࡚ᐟ୺ච␿ᶵᵓ࡟ࡼࡿ᤼㝖ࢆᅇ㑊ࡍࡿࡇ࡜࡛ᾐ

ྜ㡿ᇦ࡛࠶ࡿ E6N ࡜ E6C ࡢ 2 ࡘࡢࣔࢳ࣮ࣇࢆࡶࡕࠊ40)₶⒴࡬࡜㐍⾜ࡍࡿ (ᅗ 2) ࠋࡇࢀࡽࡢ㡿ᇦࢆ௓ࡋ࡚ᐟ୺⣽⬊ࡢᵝࠎ࡞⺮ⓑ㉁࡜⤖ ඲࡚ࡢ㧗ࣜࢫࢡᆺ HPV ឤᰁ⪅ࡀᏊᐑ㢁⒴ࢆⓎ⑕ྜࡋࠊࡑࢀࡽࡢᶵ⬟ࢆ㜼ᐖࡍࡿࡇ࡜࡛ᙧ㉁㌿᥮ࢆಁࡍࡿࢃࡅ࡛ࡣ࡞࠸ࡇ࡜ࠊࡉࡽ࡟Ꮚᐑ㢁⒴ࡢⓎ⑕࡟ࡣ㐍ࡍࡿ 43)ࠋ

HPV ឤᰁ࠿ࡽᩘ༑ᖺࡢᮇ㛫ࡀᚲせ࡛࠶ࡿ࡜࠸࠺஦
ᐇ࠿ࡽࠊᏊᐑ㢁⒴ࡢⓎ⒴࡟ࡣ HPV ௨እ࡟ࡶᵝࠎ࡞㑇1) p53 ࡢ୙ά໬ఏᏊ࣭⺮ⓑ㉁ࡢ␗ᖖࡀ㛵୚ࡋ࡚࠸ࡿ࡜⪃࠼ࡽࢀ࡚࠸

 p53 ࡣ 4 㔞యࡢ㌿෗ᅉᏊ࡛ࠊDNA ᦆയࡸప㓟⣲➼ࡿࠋ౛࠼ࡤࠊPI3KCA, Cyclin D1 ࡢቑᖜࡸ myc ࡢቑຍࡢྛ✀ࢫࢺࣞࢫࠊ⒴㑇ఏᏊࡢάᛶ໬ࠊࢸ࣓ࣟ࢔ࡢ▷ࡣṇᖖᏊᐑ㢁㒊࠿ࡽ CIN1 ࡬ࡢ㐍⾜ẁ㝵࡛ࠊHER2,

⦰➼࡛άᛶ໬ࡋᶆⓗ㑇ఏᏊࢆάᛶ໬ࡍࡿࡇ࡜࡛ࠊ⣽hTERT ࡢቑᖜࡣ CIN1 ࠿ࡽ CIN2 ࡬ࡢ㐍⾜ẁ㝵࡛ࠊ⬊ቑṪࡢ೵Ṇ (p21, GADD45 ➼ࢆ௓ࡍࡿ)ࡸ DNA ᦆ

CIN2 ࠿ࡽ CIN3 ࡬ࡢ㐍⾜ẁ㝵࡛ࡣ hTERT ࡟ຍ࠼࡚യ࡟ࡼࡿࢳ࢙ࢵࢡ࣏࢖ࣥࢺᶵ⬟ (GADD45, p48 ➼ࢆc-myc ࡢቑᖜࡀ⏕ࡌࠊCIN3 ࠿ࡽᏊᐑ㢁⒴࡬ࡢ㐍⾜ẁ௓ࡍࡿ)ࠊࡉࡽ࡟⣽⬊࡬ࡢᦆയࡀಟ᚟࡛ࡁ࡞࠸ሙྜࡣ㝵 ࡛ ࡣ PI3KCA ά ᛶ ໬ ኚ ␗ ࡸ BCL-2 (B-Cellᙉຊ࠿ࡘᣢ⥆ⓗ࡟άᛶ໬ࡋࡓ p53 ࡀ⣽⬊⪁໬ (p21,ࠋࡲࡓ࢚

PAI-1 ➼ࢆ௓ࡍࡿ)ࠊࡑࡋ࡚࢔࣏ࢺ࣮ࢩࢫ (Bax, Noxa,ࣆࢪ࢙ࢿࢸ࢕ࢵࢡ࡞␗ᖖࡶࡳࡽࢀࠊPTEN ࣉ࣮ࣟࣔPuma, PTEN ➼ࢆ௓ࡍࡿ)ࢆㄏᑟࡍࡿࠋp53 ࡣࠊṇᖖ࡞ࢱ࣮ࡢ㐣๫࣓ࢳࣝ໬ࡣ CIN2/3 ࡢ 40%ࠊᾐ₶⒴ࡢ 60%⣽⬊࡛ࡣࠊE3 ࣘࣅ࢟ࢳ࣮ࣥࣜ࢞ࢮࡢ୍ࡘ࡛࠶ࡿ

࡛ࠊTSLC1 ࣉ࣮ࣟࣔࢱ࣮ࡢ㐣๫࣓ࢳࣝ໬ࡣ CIN2/3 ࡢ

MDM2 (Mouse Double Minute 2)࡟ࡼࡾపࣞ࣋ࣝ࡟ไ

35%ࠊᾐ₶⒴ࡢ 58%᳨࡛ฟࡉࢀ࡚࠸ࡿ (ᅗ 2)ࠋࡉࡽ

ᚚࡉࢀ࡚࠸ࡿࡀࠊ୍ᗘ⣽⬊࡟ᦆയࡀ⏕ࡌࡿ࡜▐᫬࡟࡟ᡥᖹୖ⓶⣽⬊ࡢศ໬࡟㛵୚ࡍࡿ Notch1 ࡣࠊCIN1~3άᛶ໬ࡋ⣽⬊ࡢ⒴໬ࢆᢚไࡍࡿせ࡜࡞ࡗ࡚࠸ࡿࠋ

࡛Ⓨ⌧ࡀቑຍࡍࡿࡀࠊᾐ₶⒴࡛ࡣⓎ⌧ࡀῶᑡࡍࡿࡼ

 E6 ࡢ᭱ࡶ㔜せ࡞ᶵ⬟ࡢ୍ࡘࡀࡇࡢ p53 άᛶࢆᢚ࠺࡛࠶ࡿ (ᅗ 2)ࠋ

ไࡍࡿࡇ࡜࡛࠶ࡿ (ᅗ 3)ࠋ㧗ࣜࢫࢡᆺ HPV ࡢ E6 ࡣ

CLL/Lymphoma 2)ࡢቑᖜࡀ⏕ࡌࡿ (ᅗ 2)41,42)HECT ᆺ E3 ࣘ ࣅ ࢟ ࢳ ࣥ ࣜ ࢞ ࣮ ࢮ ࡛ ࠶ ࡿ E6AP
(UBE3A; Ubiquitin Protein Ligase E3A)࡜⤖ྜࡋࠊ-5-)F<#!#BE,#"&H= 12 02016    'F-1 ;hTERThT#$hTERT



E2F

NFX1-91
1 91
1
#$
%

NFκB
N

CBP
C
B
p300

p53
p
p5

E7
E

196=45
/
#$
,

TIP60
Notch1


0'"

#$0



NPM

CENP-Cγ-Tubulin0 
&- ⬇& 
⬇38:

 
+

P
Rb
Rb

Rb
R

#$0 EMT+

FADD
Pro-caspase 8
P
Pro-c
Bak
B

E6
E6
E6AP
AP
P

p107
p130
p

p21
p27
7

PDZ7;2<
7;

(!)

E6

#$ 
.*(!)

0


PLK4
NPM

4 *    G@5A$%/E6 1 E6AP ,úġ p53 >HsdXZÄɻǘȘō
ō0ȴ¥

ÌȐɦƕ,

ƾƋ

9$ E6, E7 1Þǣ*ǡƄǉŽ>ƬƂǉȴȕŽ

B

ƖEɜȂ

hTERT > NFκB 0¶ƖEÎȼ E7 1 Rb nGu{EƵ«ɢ,ȴ¥EƾƋ

B

44,45)

E6 1 C ɇɲ+ p53 /úġȼ.`LaRsJdȪ¶E¤*UivȪǪ

Ⱦ0ȴɺ

Ǩ{ZRð HPV46)

Ƽƀ/è<*Şɥ++ȍ<@CB 51) b~wz\0ğƳ¶ƖȮ
e

@/Ġ{



Binding Protein)/p300 > TIP60 (HIV-1 Tat Interactive

E6AP ,ȲġǉEñƗ

hADA3 ,=ǥƥúġ#0ÌȐEƵ«ļ0ǲŏ¶ƖEɦƕ

B

50)

B

47,48,49)

șćEɦƕ

B,+

p53 0H[`|EƵ«* p53 /?Bɢ

.Ǵ

¥EƾƋ

9$Ġ{ZRð

Ƌ

E6-E6AP Ȳġǉ1hTERT 0B NFX1-91 (Nuclear Transcription
īśǯ/ǲŏļ myc/Max  hTERT

B 52)

9$ E6 1 hTERT 0o~x^0H[`|EɜȂ

0?/Ġ{ZRð HPV E6 1ȈŞ/=Ĵōǲ¾EƾƋ

0 hTERT 0șćEɜȂo~x^/{R|dC hTERT 0ǲŏʀ

p53 0¶ƖEƵ«Ş/=ĕɌ/ p53 0¶ƖEƵ«

HPV E6 1

Factor, X-Box Binding 1-91)0ylQ`/?Bȴ

p53 ¶Ɩņ/ MDM2 /úġ* p53
B p14 /úġǉĮȾ+17,F-þŢC.
B (Ǝ 3) ɷ2*Ġ{ZRð HPV E6 1

EV

B hTERT 1»ĮȾǹ0Ĉ@C$ĮȾ+șćZRð?3Ǩ{ZRð HPV E6 1 CBP (CREB
Protein, 60kDa),

85%ź0ÆĮȾ+b~wHǤ0Ņ/ȥƍ.b~wz\Ġ¶ƖB p53 0ȴ¥1ƾƋ.,ɏ@/.'*BEǪB,+ĮȾřËE

@.BǴļȷ0ǟƠ>ÆǴļ0¶ƖEŲ

E6AP 0ÈōȅƖEȷB,+ p53 0ylQ`

HPV E6 1

PDZ ȹɚǘȘşŔĮȾ0ñ

B 53) ƛɔ@#0ǲŏE¶Ɩ

/?B, kdƚŽļÖ÷Ȯ³ĮȾ0ȪĿ/1

B

Rb/p16 óɼ0Ȫ¶,b~wz\0¶ƖŰ.,=ȥɥ+B2) b~wz\¶Ɩ,ĮȾ0ȪĿ

HPV 1ċŤ

óɼEȪ¶ E6 b~wz\E¶Ɩ b~wH1 GGGTTA ɕ 1000 ¦ȜȰ$ȕɹ+,+şŔĮȾ0ȪĿEɜȂƬƂǉɇǖ+ƬƂǉEȹč

 E6-E6AP Ȳġǉ1B

B E7  Rb

b~wH1ĮȾȴ

B

B

54)

Fas XSf|/?BHsd

ɺ0Ƿ/ǕŠīśǯ/ĮȾ1ĮȾɿ/ŀA

X Z / Ş ɥ . FADD (Fas-Associated Via DeathƼƀǩľ#0$<b~wHǤ0Ņ1ÆĮ

Domain), o~OZj\ 8 > ɢB-6-.ĮȾZd}Z⇃ᮏ኱Ꮫ་Ꮫ㒊ಖ೺Ꮫ⛉⣖せ➨ 12 ྕ㸦2016㸧    ྜྷᮏ㈼ྐ ௚࡟ᑐࡋ࡚࣑ࢺࢥࣥࢻࣜ࢔࠿ࡽࡢࢩࢺࢡ࣒ࣟ c ࡢᨺฟ

CYLD (Cylindromatosis; ప㓟⣲⎔ቃୗ࡛ NFțB ⤒㊰ࢆ ௓ ࡋ ࡓ ࢔ ࣏ ࢺ ࣮ ࢩ ࢫ ࡟ 㔜 せ ࡞ Bak (Bcl-2

ࢆ ά ᛶ ໬ ࡍ ࡿ )ࢆ ୙ ά ໬ ࡍ ࡿ ࡇ ࡜ ࡸ ࠊ E6 ࡟ ࡼ ࡿ

Homologous Antagonist/Killer)࡜⤖ྜࡋࠊࡑࡢᶵ⬟ࢆ

NFX1-91 (NFțB ࢆᢚไࡍࡿ p105 ࡢ㌿෗ࢆάᛶ໬ࡍ

ࠋࡇࡢࡼ࠺࡟ HPV E6 ࡣ p53 ࡟ຍࡿ)ࡢศゎಁ㐍ࡶ㛵୚ࡍࡿࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿ

㜼ᐖࡍࡿ (ᅗ 3)

55,56)

ࠋ࠼ࠊp53 㠀౫Ꮡᛶࡢ⣽⬊Ṛࡶ㜼ᐖࡍࡿࡇ࡜࡛ᐟ୺⣽43,59)⬊࡛ࡢ⏕Ꮡྍ⬟࡞⎔ቃࢆᩚ࠼ࡿࠋ

5) E6 ࡟ࡼࡿ␗ᖖ࡞⣽⬊ศ໬ࡢㄏᑟ ⣽⬊ศ໬ࡢᶵᗎ࡟ࡘ࠸࡚ࡣᮍࡔࡑࡢヲ⣽ࡣ᫂ࡽ࠿3) Bak ࡢ୙ά໬࡜࢔࣏ࢺ࣮ࢩࢫᢚไ

࡟࡞ࡗ࡚࠸࡞࠸ࡀࠊHPV E6 ࡣ⣽⬊ศ໬ࢆᢸ࠺࠸ࡃ

 Bak ࡣᵝࠎ࡞ࢫࢺࣞࢫ࡟ᛂࡌ࡚࣑ࢺࢥࣥࢻࣜ࢔ࢆ

ࡘ࠿ࡢ⺮ⓑ㉁ࡢᶵ⬟ࢆ㜼ᐖࡋࠊᐟ୺⣽⬊ࢆ⮬㌟ࡢ⏕௓ࡋࡓ࢔࣏ࢺ࣮ࢩࢫࢆάᛶ໬ࡍࡿࠋ࢔࣏ࢺ࣮ࢩࢫࢩ

Ꮡ࡟᭷฼࡞⎔ቃ࡟ኚ᭦ࡍࡿࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿࠋ

ࢢࢼࣝࡀධࡿ࡜ࠊάᛶ໬࢝ࢫࣃ࣮ࢮ 8 ࡟ࡼࡾάᛶ໬ 㧗 ࣜ ࢫ ࢡ ᆺ HPV E6 ࡣ ERC-55 (Endoplasmic

ࡋࡓ Bid (BH3 Interacting Domain Death Agonist)࡜ Bak,

Reticulum Calcium-Binding Protein, 55kD; ࢝ࣝࢩ࣒࢘

Bad (BCL2-Associated Agonist of Cell Death), Puma⤖ྜ⺮ⓑ㉁), E6-TP1 (E6-Targeted Protein 1 ; GTPase(P53 Up-Regulated Modulator of Apoptosis)ࡀ࣑ࢺࢥࣥ

άᛶ໬⺮ⓑ㉁), paxillin (᥋╔Ⅼ⺮ⓑ㉁)࡜⤖ྜࡋࠊࡇࢻࣜ࢔࡬⛣ືࡋࠊBcl-2 ࣇ࢓࣑࣮ࣜࢆᢚไࡍࡿࠋBcl-

ࢀࡽࡢᶵ⬟ࢆ㜼ᐖࡍࡿࡇ࡜࡛ゅ໬⣽⬊ࡢศ໬␗ᖖࢆ

2 ࣇ࢓࣑࣮ࣜࡢᢚไ࡟ࡼࡾ࣑ࢺࢥࣥࢻࣜ࢔࠿ࡽᨺฟ

ㄏᑟࡍࡿࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿ 43)ࠋࡲࡓ Nees ࡽࡣࠊࡉࢀࡓࢩࢺࢡ࣒ࣟ c ࡣࠊApaf-1 ࡜࡜ࡶ࡟࢝ࢫࣃ࣮ࢮ

Ꮚᐑ㢁㒊ࡢゅ໬⣽⬊࡟ E6 ࠾ࡼࡧ E7 ࢆ㐣๫Ⓨ⌧ࡋ࣐

9 ࢆάᛶ໬ࡋࠊࡇࢀࡀ࢔࣏ࢺ࣮ࢩࢫࢆᐇ⾜ࡍࡿ࢝ࢫ࢖ࢡࣟ࢔ࣞ࢖ゎᯒࢆࡋࡓ⤖ᯝࠊTGFȕ2 ࡢⓎ⌧ࣞ࣋ࣝࣃ࣮ࢮ 3/7 ࢆษ᩿࣭άᛶ໬ࡍࡿࠋపࣜࢫࢡᆺ࠾ࡼࡧ

ࡢῶᙅ࡜ TGFȕ ⤒㊰㜼ᐖ࡟ࡼࡿゅ໬⣽⬊ࡢศ໬␗ᖖ

㧗ࣜࢫࢡᆺ HPV E6 ࡣ Bak ࡟⤖ྜࡋࠊศゎࢆಁ㐍ࡍࢆሗ࿌ࡋࡓ 60)ࠋࡿࡇ࡜࡛ࠊp53 㠀౫Ꮡᛶ࡟ࡶ࢔࣏ࢺ࣮ࢩࢫࢆᢚไࡍ ࡉࡽ࡟㧗ࣜࢫࢡᆺ HPV E6 ࡣࠊゅ໬⣽⬊ࡢศ໬࡟ࡿ (ᅗ 3) ࠋ㛵୚ࡍࡿ Notch ⤒㊰␗ᖖࢆᣍࡃࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸

43)

ࡿ (ᅗ 3)ࠋNotch ࢩࢢࢼࣝࡣ Notch ཷᐜయ࡟ DSL ࣜ4) PDZ ࢻ࣓࢖ࣥಖ᭷⺮ⓑ㉁ࡢ㜼ᐖ࢞ࣥࢻࡀ⤖ྜࡍࡿࡇ࡜࡛㛤ጞࡋࠊNotch ཷᐜయࡢ⣽ ඲࡚ࡢ㧗ࣜࢫࢡᆺ HPV E6 ࡣ C ᮎ࡟ PDZ ࢻ࣓࢖⬊ෆࢻ࣓࢖࡛ࣥ࠶ࡿ NICD ࡀ Ȗ ࢭࣞࢡࢱ࣮ࢮ࡟ࡼࡾ

ࣥ⤖ྜ㡿ᇦࢆಖ᭷ࡍࡿࠋPDZ ࢻ࣓࢖ࣥࢆᣢࡘ⺮ⓑ㉁ษ᩿ࡉࢀࠊNICD ࡀ᰾࡬⛣⾜ࡍࡿࡇ࡜࡛ Hes1/5 (Hes(hDLG, hScribble, MUPP1, MAGI, PSD95 ➼)ࡣࠊ⣽⬊Family BHLH Transcription Factor 1/5)➼ࡢ㌿෗ࢆάᛶᴟᛶࡸ⣽⬊㛫ࡢ᥋╔ࠊ⺮ⓑ㉁」ྜయࢆᙧᡂࡍࡿࡓࡵ

໬ࡍࡿࠋNotch1 ࡣゅ໬⣽⬊࡟࠾࠸࡚ p21 Ⓨ⌧ࢆㄏᑟࡢ㊊ሙ࡜ࡋ࡚ᶵ⬟ࡍࡿࡇ࡜ࡀ▱ࡽࢀ࡚࠸ࡿࠋࡑࡢࡓ

ࡍࡿࡇ࡜࡛⣽⬊ቑṪࢆ೵Ṇࡋࠊࡉࡽ࡟ゅ໬⣽⬊ࡢึࡵ HPV E6 ࡣࡇࢀࡽ PDZ ࢻ࣓࢖ࣥ⤖ྜ㡿ᇦࢆಖ᭷ࡍ

ᮇศ໬ࢆㄏᑟࡍࡿ࡜࠸࠺ሗ࿌ࡀ࠶ࡿ 61)ࠋᏊᐑ㢁⒴࡛

ࡿ⺮ⓑ㉁ࡢᶵ⬟ࢆ㜼ᐖࡍࡿࡇ࡜࡛ࠊ⣽⬊ᴟᛶࡢ႙ኻ

ࡣࠊNotch1 ࡣపศ໬࠿ࡘᾐ₶㒊࡛ࡼࡾⓎ⌧ࡀῶᑡࡲࡸ EMT (Epithelial-Mesenchymal Transition; ୖ⓶㛫ⴥࡓࡣ႙ኻࡋࠊࡇࡢ Notch1 Ⓨ⌧ῶᑡࡢ୍ᅉ࡟ HPV E6ࠋࡢస⏝ࡀ࠶ࡿ 62,63)ࠋࡘࡲࡾ HPV E6 ࡣ p53 ࡢࣘࣅ࢟ 㧗ࣜࢫࢡᆺ HPV E6 ࡣ PDZ ࢻ࣓࢖ࣥ౫Ꮡᛶ࡟

ࢳࣥ໬ࢆಁ㐍ࡋศゎࡍࡿࡇ࡜࡛ p53 ࢆ୙ά໬ࡋࠊp53

NFțB (Nuclear Factor of Kappa Light Polypeptide Geneࡢᶆⓗ㑇ఏᏊ࡛࠶ࡿ Notch1 Ⓨ⌧ࢆᢚไࡍࡿ 1,64)ࠋࡇ

Enhancer In B-Cells)ࢆάᛶ໬ࡍࡿ (ᅗ 3)58)ࠋNFțB ࡣࡢࡼ࠺࡟ HPV E6 ࡣࠊp53 ࡢศゎ࡜ྠ᫬࡟ Notch1 Ⓨࢧ࢖ࢺ࢝࢖ࣥࡸࢣࣔ࢝࢖ࣥ࡟཯ᛂࡋ࡚άᛶ໬ࡋࠊ᰾

⌧ࡢῶᑡࢆᘬࡁ㉳ࡇࡍࡇ࡜࡛ࠊᐟ୺⣽⬊ࡢ␗ᖖቑṪ࡬⛣⾜ࡋࡓ NFțB ࡀᵝࠎ࡞㑇ఏᏊࢆㄏᑟࡍࡿࡇ࡜࡛

࡜ศ໬␗ᖖࢆ୍ᗘ࡟⋓ᚓࡍࡿࡇ࡜ࡀྍ⬟࡛࠶ࡿ࡜⪃࢔࣏ࢺ࣮ࢩࢫᢚไࠊప㓟⣲≧ែ࡬ࡢ᢬ᢠᛶࡢ⋓ᚓࠊ࠼ࡽࢀࡿࠋ㌿᥮)ࢆᘬࡁ㉳ࡇࡍࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿ (ᅗ 3)

1,57)

EMT ࡞࡝ᐟ୺⣽⬊ࡢ⏕Ꮡࢆಁ㐍ࡍࡿࠋE6 ࡟ࡼࡿNFțB ࡢάᛶ໬࡟ࡣࠊE6 ࡀ⬺ࣘࣅ࢟ࢳࣥ໬㓝⣲-7-⇃ᮏ኱Ꮫ་Ꮫ㒊ಖ೺Ꮫ⛉⣖せ➨ 12 ྕ㸦2016㸧    ྜྷᮏ㈼ྐ ௚

2. E7 ࡢⓎ⒴⬟ࡸ DNA ྜᡂࠊศ໬␗ᖖ (Rb ୙ά໬࡟ࡼࡿάᛶ໬ Akt

 HPV E7 ࡣ⣙ 100 ಶࡢ࢔࣑ࣀ㓟࠿ࡽ࡞ࡿ⺮ⓑ㉁࡛

ࡀ᰾ᑠయ⺮ⓑ㉁ࡢ nucleophosmin ࡢⓎ⌧ࢆஹ㐍ࡍࡿ

࠶ࡿࠋE7 ࡢ N ᮎഃ࡟ࡣࠊSV40 largeT ࡸ࢔ࢹࣀ࢘࢖

ࡇ࡜࡟ࡼࡿ)➼ࢆㄏᑟࡍࡿ (ᅗ 3)43,68)ࠋࡇࡢ HPV E7

ࣝࢫ E1A ࡶಖ᭷ࡍࡿ CR1/2 㡿ᇦࡀಖᏑࡉࢀ࡚࠸ࡿࠋ

࡟ࡼࡿ Rb ୙ά໬ࡣࠊపࣜࢫࢡᆺ࡜ẚ࡭㧗ࣜࢫࢡᆺゅ໬⣽⬊࡟ᑐࡋ࡚ࡣࠊ㧗ࣜࢫࢡᆺ HPV E6 ༢⊂࠾ࡼࡢ᪉ࡀࡼࡾᙉࡃ୙ά໬ࡍࡿࡇ࡜ࡀศ࠿ࡗ࡚࠸ࡿࠋࡲ

ࡧ E7 ༢⊂࡛ࡣഹ࠿࡞୙Ṛ໬⬟ࢆ♧ࡍࡢࡳ࡛࠶ࡿࡀࠊ

ࡓ HPV E6 ࡶ Rb ࡢࣜࣥ㓟໬ࢆಁ㐍ࡍࡿࡇ࡜࡛ Cyclin

E6 ࡜ E7 ࡣ༠ㄪࡍࡿࡇ࡜࡛ゅ໬⣽⬊࡟㧗࠸୙Ṛ໬⬟A ࡸ E2F ࡢⓎ⌧ࢆஹ㐍ࡋࠊ⣽⬊࿘ᮇ㐍⾜࡟㛵୚ࡍࡿ

ࢆ୚࠼ࡿ

65)

ࠋຍ࠼࡚ࠊ㏻ᖖࠊᡥᖹୖ⓶⣽⬊ࡣᇶᗏ⣽43)ࠋຍ࠼࡚㧗ࣜࢫࢡᆺ HPV E7 ࡢሙྜࡣࠊᇶᗏ⣽⬊⬊࣭ഐᇶᗏ⣽⬊ࡀ⣽⬊ศ⿣ࡋୖᒙ࡟⛣ືࡍࡿ࡟ࡘࢀ

ᒙࡢ⣽⬊࿘ᮇࢆไᚚࡍࡿ p107ࠊศ໬ࡢ㐍ࢇࡔୖ㒊ࡢ࡚⣽⬊࿘ᮇࡢ೵Ṇ࡜ศ໬ࢆ⾜࠺ࡀࠊE7 ࡣ⣽⬊࿘ᮇࢆ⣽⬊ᒙࡢ⣽⬊࿘ᮇࢆไᚚࡍࡿ p130 ࡜⤖ྜࡋࠊࡇࢀࡽ

෌㛤ࡋᐟ୺⣽⬊ࡢ DNA 」〇⿦⨨ࢆ฼⏝ࡍࡿࡇ࡜࡛

ࢆ୙ά໬ࡍࡿࡇ࡜࡛ E2F4/5 ࡟ࡼࡿ⣽⬊࿘ᮇࡢ㐍⾜⮬㌟ࡢࢤࣀ࣒ࢆຠ⋡ⓗ࡟ቑᖜࡍࡿ

ࠋࢆᣍࡃ (୍᪉ࠊపࣜࢫࢡᆺ HPV E7 ࡣ p107, p130 ࡟

66)ᑐࡋ࡚ⱝᖸࡢ㜼ᐖస⏝ࢆ♧ࡍ)69,70)ࠋࡉࡽ࡟ E7 ࡣࠊ1) Rb ࡢ㜼ᐖ࡟ࡼࡿ⣽⬊࿘ᮇࡢ␗ᖖ

CDK1/2 㜼ᐖᶵ⬟ࢆࡶࡘ p21, p27 ࡟┤᥋⤖ྜࡋࡑࢀ Rb ࡣ⣽⬊࿘ᮇࡢไᚚࢆᢸ࠺⺮ⓑ㉁࡛ࠊRb ࡢ୙άࡽࡢᶵ⬟ࢆ㜼ᐖࡍࡿࡇ࡜࡛ࠊ㏻ᖖࡣ⣽⬊࿘ᮇ౫Ꮡᛶ

໬ࡣ p53࣭ࢸ࣓࣮ࣟࣛࢮάᛶ໬࡜࡜ࡶ࡟ᵝࠎ࡞⒴࡛࡟άᛶࢆᣢࡘ CDK1/2 ࡢάᛶࢆᣢ⥆ⓗ࡟⥔ᣢࡋࠊ⣽

ඹ㏻ࡋ࡚ࡳࡽࢀࡿศᏊ⏕≀Ꮫⓗ␗ᖖ࡛࠶ࡿࠋRb ࡣ⣽⬊࿘ᮇࡢ⬺ไᚚࢆᣍࡃ 71,72)ࠋࡇࡢࡼ࠺࡟㧗ࣜࢫࢡᆺ⬊࿘ᮇࡢ G1 ᮇ࡟㌿෗ᅉᏊ E2F ࡸࢡ࣐ࣟࢳࣥࣜࣔࢹ

HPV E7 ࡣࠊపࣜࢫࢡᆺ࡜ẚ࡭࡚ຠ⋡ࡼࡃ⣽⬊࿘ᮇࣜࣥࢢᅉᏊ SWI-SNF 」ྜయ࡟⤖ྜࡍࡿࡇ࡜࡛ࠊE2F

ࡢ㛤ጞࡸ DNA ྜᡂࢆㄏᑟࡍࡿࠋ

ᶆⓗ㑇ఏᏊࡢ㌿෗ࢆᢚไࡋ⣽⬊࿘ᮇࢆ೵ṆࡍࡿࠋRb
ࡣ AB ࣏ࢣࢵࢺ㡿ᇦࢆ௓ࡋ࡚ E2F ࡜⤖ྜࡍࡿࡀࠊG12) ᐟ୺⣽⬊ࡢࢤࣀ࣒୙Ᏻᐃᛶࡢㄏᑟ

୰ᮇ࡟࡞ࡿ࡜ AB ࣏ࢣࢵࢺ㡿ᇦࡀ Cyclin D-CDK4/6

 ࢤࣀ࣒୙Ᏻᐃᛶࡣ⭘⒆࡟ࡳࡽࢀࡿ≉ᚩⓗ࡞⌧㇟࡛ࠊ

(Cyclin-Dependent Kinase 4/6)」ྜయ࡟ࡼࡾࣜࣥ㓟໬ᵝࠎ࡞ศᏊ⏕≀Ꮫⓗ␗ᖖࡢ⋓ᚓࢆಁ㐍ࡋ⒴⣽⬊࡟୙ࡉࢀࠊE2F ࡀ Rb ࠿ࡽ㐟㞳ࡋᶆⓗ㑇ఏᏊࢆάᛶ໬ࡍ

฼࡞⎔ቃୗ࡛ࡶࡑࢀ࡟ᡴࡕ຾ࡕࠊ⭘⒆⣽⬊ࡢ㐍⾜࡟ࡿࡇ࡜࡛⣽⬊࿘ᮇࡣ S ᮇ࡟㐍⾜ࡍࡿࠋE2F ࡣ Cyclinᐤ୚ࡍࡿ⌧㇟࡛࠶ࡿࠋ㏻ᖖࡢ⣽⬊࡟ഛࢃࡗ࡚࠸ࡿ⣽A/E ࡸᵝࠎ࡞⣽⬊ቑṪಁ㐍ᅉᏊࡢⓎ⌧ࢆஹ㐍ࡍࡿࠋ⬊࿘ᮇไᚚᶵᵓࡸ DNA ಟ᚟ᶵᵓࠊᰁⰍయศ㓄ᶵᵓ

Cyclin A ࡣ CDK1/2 ࡜ࠊCyclin E ࡣ CDK2 ࡜」ྜయࡀ◚⥢ࡍࡿࡇ࡜࡛ࠊ㑇ఏᏊኚ␗⋡ࡢቑຍ࡜ᰁⰍయ୙

ࢆᙧᡂࡋࠊDNA 」〇ᅉᏊࡢࣜࣥ㓟໬ࡸ Rb ࡢࣜࣥ㓟Ᏻᐃᛶࡀ⏕ࡌࠊࢤࣀ࣒୙Ᏻᐃᛶ࡬࡜⮳ࡿ 73,74)ࠋ

໬ࢆ⾜࠺ࡇ࡜࡛⣽⬊࿘ᮇࢆ㐍⾜ࡉࡏࡿࠋࡋ࠿ࡋ DNA ⣽⬊ෆ࡟ࡣṇᖖ࡞⣽⬊࿘ᮇࢆ⥔ᣢࡍࡿࡓࡵࠊไ㝈ᦆയ➼࡛ G1 ࢳ࢙ࢵࢡ࣏࢖ࣥࢺࡀάᛶ໬ࡍࡿ࡜ࠊάⅬ (୙ྍ㏫ⓗ࡞ S ᮇ㐍⾜ࢆチྍࡍࡿᶵᵓ)ࠊG2/M ᮇᛶ໬ p53 ࡀ p21 ࡸ p27 ࢆ௓ࡋ࡚ CDK1/2 ࡢᶵ⬟ࢆ㜼ࢳ࢙ࢵࢡ࣏࢖ࣥࢺ (ṇ☜࡞ DNA 」〇ࡀ⾜ࢃࢀ࡚࠸ᐖࡋࠊ⣽⬊࿘ᮇࢆ೵ṆࡍࡿࠋDNA ಟ᚟ᚋ࡟⣽⬊࿘ᮇࡿࡇ࡜ࢆ☜ㄆࡋ M ᮇ㐍⾜ࢆチྍࡍࡿᶵᵓ)ࠊ⣳㗽యࢆ෌㛤ࡍࡿࠊ࠶ࡿ࠸ࡣಟ᚟ࡋࡁࢀ࡞࠸ DNA ᦆയࡀࢳ࢙ࢵࢡ࣏࢖ࣥࢺ (ಸຍᰁⰍయࢆᆒ➼࡟ศ㓄ࡍࡿࡓ⏕ࡌࡓሙྜࡣ࢔࣏ࢺ࣮ࢩࢫࢆㄏᑟࡍࡿࡇ࡜࡛ࠊDNA

ࡵࠊ୰ᚰయ࠿ࡽఙࡧࡓᚤᑠ⟶ࡀ඲ᰁⰍయࡢືཎయ࡟

␗ᖖࢆፉ⣽⬊࡟ᘬࡁ⥅ࡄࡇ࡜ࢆ㜵࠸࡛࠸ࡿࠋṇ☜࡟௜╔ࡋ࡚࠸ࡿࡇ࡜ࢆ☜ㄆࡋ⣽⬊㉁ศ⿣㛤ጞࢆ

67)

 HPV E7 ࡣ Rb ࡢ AB ࣏ࢣࢵࢺ㡿ᇦ࡬ࡢ⤖ྜࡸࠊチྍࡍࡿᶵᵓ)࡜࠸ࡗࡓࢳ࢙ࢵࢡ࣏࢖ࣥࢺࡀᏑᅾࡍ

Calpain, Cullin 2 ࢆࣜࢡ࣮ࣝࢺࡋ Rb ࡢษ᩿࣭ศゎࢆࡿࠋ౛࠼ࡤ DNA ᦆയࡀ⏕ࡌࡿ࡜ࠊᦆയ㒊఩࡟ࣜࢡ⾜࠺ࡇ࡜࡛ࠊE2F1/2/3 ࡢᜏᖖⓗ࡞άᛶ໬ࢆᣍࡁࠊࡑࣝ ࣮ ࢺ ࡉ ࢀ ࡓ ATM (Ataxia Telangiectasia Mutated)ࡢ⤖ᯝ Cyclin A/E-CDK 」ྜయࡢ⵳✚ࡸ DNA ࣏࣓ࣜ/ATR (Ataxia Telangiectasia And Rad3-Related Protein)࣮ࣛࢮ ĮࠊPCNA (Proliferating Cell Nuclear Antigen)ࠊ

ࡀ ά ᛶ ໬ ࡋ ࠊ p53 ࡢ Ᏻ ᐃ ໬ ࣭ ά ᛶ ໬ ࡸ CHK1/2

hTERT ➼ࡢⓎ⌧ஹ㐍࡟ࡼࡿ⣽⬊࿘ᮇࡢ S ᮇ࡬ࡢ㐍⾜(Checkpoint Kinase 1/2)άᛶ໬ࢆ௓ࡋ࡚ G1/S ᮇࡢไ-8-⇃ᮏ኱Ꮫ་Ꮫ㒊ಖ೺Ꮫ⛉⣖せ➨ 12 ྕ㸦2016㸧    ྜྷᮏ㈼ྐ ௚

㝈Ⅼ࠶ࡿ࠸ࡣ G2/M ᮇࢳ࢙ࢵࢡ࣏࢖ࣥࢺࡀάᛶ໬ࡉ

࣮ࢽࣥࢢ᳨ᰝ࡜ࡋ࡚ࡢ⣽⬊デࡸ࣡ࢡࢳࣥ᥋✀ࡢᬑཬ

75)

ࠋ๓㏙ࡋࡓࡼ࠺࡟ࠊHPV࡟ࡼࡾࠊඛ㐍ᅜ࡟࠾ࡅࡿᏊᐑ㢁⒴ࢆཎᅉ࡜ࡋࡓṚஸ

E6 ࡣࢳ࢙ࢵࢡ࣏࢖ࣥࢺᶵᵓࡢせ࡛࠶ࡿ p53 ࢆࣘࣅ⪅ᩘࡣῶᑡഴྥ࡟࠶ࡿࠋࡑࢀ࡟ࡶ࠿࠿ࢃࡽࡎࠊᏊᐑ

࢟ࢳࣥ໬࣭ศゎࡋࠊHPV E7 ࡣ G1/S ᮇࢳ࢙ࢵࢡ࣏࢖

㢁⒴ࡣ౫↛࡜ࡋ࡚ዪᛶࡢ⒴࡟ࡼࡿṚஸཎᅉࡢ➨஧఩ࣥࢺࡢไ㝈Ⅼࢆᢸ࠺ Rb ࢆ୙άᛶ໬ࡍࡿ (ᅗ 3)ࠋࢳ࡛࠶ࡾࠊ᪥ᮏ࡟࠾࠸࡚ࡣࡑࡢᝈ⪅ᩘࡣቑຍഴྥ࡟࠶

࢙ࢵࢡ࣏࢖ࣥࢺࡢ◚⥢ࡀ㉳ࡁࡓ⣽⬊࿘ᮇ࡛ࡣࠊࢤࣀ

ࡿࠋࡇࡢࡼ࠺࡞⌧≧ࢆ㋃ࡲ࠼ࡿ࡜ࠊࡉࡽ࡟ヲ⣽࡞Ꮚ࣒ࡢᦆയࡸ୙᏶඲࡞ DNA 」〇ࢆ⿕ࡗࡓࡲࡲ⣽⬊࿘ᐑ㢁⒴ࡢⓎ⒴ᶵᗎࡸ HPV ᣢ⥆ឤᰁࡢᶵᗎࡢゎ᫂࡟ᮇࡀ㐍⾜ࡋ࡚࠸ࡃࡓࡵࠊ㑇ఏᏊኚ␗ࡢ⵳✚ࡸᰁⰍయࡼࡿ᪂ࡓ࡞どⅬ࡟ᇶ࡙࠸ࡓ἞⒪᪉ἲ࣭デ᩿᪉ἲࡢ㛤ࡢศ㓄␗ᖖࠊ஧ືཎయᰁⰍయ (2 ࡘࡢࢭࣥࢺ࣓ࣟ࢔

Ⓨࡀᮇᚅࡉࢀࡿࠋ౛࠼ࡤᢠ HPV ἞⒪⏝࣡ࢡࢳࣥ࡜ࡋ

ࢆ᭷ࡍࡿ≧ែ)ࡢᙧᡂࠊศ⿣ᚋᮇᯫᶫ (p53 ୙ά໬⣽࡚ࠊ࢝ࣉࢩࢻ࡛࠶ࡿ L1 ࡟ࠊࡍ࡭࡚ࡢᏊᐑ㢁⒴⣽⬊࡛⬊࡟࠾࠸࡚ࠊࢸ࣓ࣟ࢔ࡀ▷ᑠ໬ࡋಖㆤࡉࢀ࡚࠸࡞࠸

Ⓨ⌧ࡋ࡚࠸ࡿࡇ࡜ࡀ⪃࠼ࡽࢀࡿ E6, E7 ࢆ⤌ࡳྜࢃࡏᰁⰍయᮎ➃㛫ࡢ⼥ྜ࣭ษ᩿࣭ᯫᶫᙧᡂࡀ㉳ࡇࡿ⌧㇟ࡓ࣓࢟ࣛ VLP (CVLP: chimeric HPV-like particle)ࡢ㛤࡛ࠊᰁⰍయࡢ㌿ᗙ࣭ᤄධ࣭ḞኻࢆㄏⓎࡍࡿ)ࠊᰁⰍయ

Ⓨ࣭⮫ᗋヨ㦂ࡀ⾜ࢃࢀ࡚࠸ࡿ 1)ࠋࡇࡢࡼ࠺࡟ HPV ࢆࡢ␗ᩘᛶࢆᣍࡁࠊ᭱⤊ⓗ࡟ࢤࣀ࣒୙Ᏻᐃᛶ࡟⮳ࡿ 76)ࠋ୰ᚰ࡜ࡋࡓᏊᐑ㢁⒴ࡢⓎ⒴ᶵᗎࡢゎ᫂ࡣ௒ᚋࡢᏊᐑ ᰁⰍయ୙ᏳᐃᛶࡣࠊᏊᐑ㢁⒴ࡢ๓⒴≧ែ࡜࠸࠺᪩

㢁⒴἞⒪ࡢᡂ⦼ྥୖ࡟ᚲ㡲࡛࠶ࡿࡇ࡜ࡀ⪃࠼ࡽࢀࡿࠋ

ࢀࠊ⣽⬊࿘ᮇࡀ೵Ṇࡍࡿᮇẁ㝵࠿ࡽࡳࡽࢀࡿ␗ᖖ࡛ࠊࡇࢀࡣ HPV E6 ࡜ E7 ࡀ

V. ཧ⪃ᩥ⊩ྛࠎ⊂❧ࡋ࡚ច㉳ࡋ࡚࠸ࡿࡇ࡜ࡀ▱ࡽࢀ࡚࠸ࡿ (ᅗ3) ࠋ౛࠼ࡤࠊヲ⣽࡞ᶵᗎࡣ୙࡛᫂࠶ࡿࡀࠊ㧗ࣜࢫࢡ
77)

ᆺ HPV E7 ࡣ E2F άᛶ໬ࡸ Cyclin A/E-CDK2 」ྜయ

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carcinoma and its prevalence in cancer biopsy samples

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BULLETINOF
KUMAMOTO UNIVERSITYSCHOOL OF HEALTH SCIENCES
THE 12th ISSUE (2016)
CONTENTS
Review
Molecular carcinogenesis of cervical cancer ------------------------- Masafumi Yoshimoto et al. ----- 1

KUMAMOTO UNIVERSITY SCHOOL OF HEALTH SCIENCES